A. Pulmonary Host Defense and the Pathogenesis of Pneumonia
In view of the constant challenge to the respiratory tract from inhaled or aspirated microbes, and the deleterious consequences of unchecked infection, an efficient system of pulmonary antimicrobial defense is obviously important to health. Microbes which elude the mechanical defenses offered by the upper respiratory tract and airways reach the alveoli. Here, the alveolar macrophage normally serves as the defender of mucosal sterility, patrolling the alveolar surface and clearing organisms by phagocytosis and intracellular killing. M. Lohmann-Matthes et al., Eur. Respir. J. 7:1678-1689 (1994)!. If the microbial load exceeds the local clearance capacity of the resident alveolar macrophages, the macrophages can elaborate chemotactic factors which recruit circulating neutrophils to the airspaces and activate their phagocytic and microbicidal activities.
Although phagocytic cells are capable by themselves of microbial ingestion, the efficiency of this process is enhanced by the presence of various soluble molecules (opsonins) which coat the organisms and mediate their attachment to surface receptors on the phagocyte. These opsonins include immunoglobin as well as factors which coat microbes nonspecifically, such as the complement fragment C3b, surfactant protein A, and fibronectin. Likewise, phagocytosis and intracellular killing are further augmented by a variety of activating agents, including colony stimulating factors, chemokines, and lipids. Unfortunately, qualitative or quantitative impairment of any component of these defenses can compromise bacterial clearance and predispose to pneumonia. See, e.g., J Langermans et al., J. Immunol. Methods 174:185-194 (1994)!.
B. Significance of Bacterial Pneumonia
In industrialized nations, pneumonia is associated with greater morbidity and mortality than any other type of infection. Overall, it is the sixth leading cause of death in the United States. In adults greater than 65 years of age, it is the fourth most common reason for hospitalization. Among hospital-acquired infections, pneumonia is the second most common in incidence and the most commonly fatal.
Bacteria are the etiologic pathogens in a substantial proportion of community-acquired pneumonias and in the great majority of nosocomial pneumonias. Frequently, enteric Gram-negative organisms are the etiologic microbes responsible for both types of pneumonia. Gram-negative pneumonias are generally thought to result from microaspiration of oral secretions, and are therefore particularly likely in individuals demonstrating oropharyngeal colonization with these organisms. This is especially common in hospitalized patients, particularly those in intensive care units, but also occurs in alcoholics, patients with underlying systemic illness or impairments in host defense, and those with chronic pulmonary disease. S. Nelson et al., Clin. Chest Med. 16:1-12 (1995)!.
C. Antibiotic Therapy
Due to the widespread use and frequent over-prescribing of antimicrobial agents, there is an increasing incidence of microbes acquiring drug-resistance. In other words, organisms typically susceptible (i.e., inhibited or killed) to a particular antimicrobial agent are no longer susceptible. This is especially important with regard to the use of antibiotics in the treatment of bacterial infections.
Acquired drug resistance is usually caused by a mutation within the genome of the microbe or by the acquisition of a plasmid. For example, one of the major mechanisms of resistance to the .beta.-lactam antibiotics, including penicillins, is the production of .beta.-lactamases. Moreover, resistance to one member of a class of agents (e.g., the aminopenicillin ampicillin) can result in complete cross-resistance to other members of that class (e.g., the aminopenicillin amoxicillin).
Antibiotic pressure in certain patient populations (e.g., patients with underlying systemic illness or impairments in host defense) has contributed to the development of infections with multi-drug resistant organisms, the eradication of which is increasingly difficult. One factor contributing to antibiotic pressure is the widespread use of antibiotics in the hospital setting, especially in the critical care units. Indeed, physicians are frequently forced to utilize antibiotic regimens comprising multiple agents to combat such infections or to use broad-spectrum agents (e.g., Primaxin.RTM., Merck) generally reserved for the most serious infections.
What is needed is a means for enhancing pulmonary defense capabilities that either requires no antibiotics or can be used to augment antibiotic treatment. The enhancement means should be efficacious in the treatment and prevention of bacterial pneumonia in those patients who are especially susceptible thereto, should have a rapid onset of action, and should not elicit immunological reactions in the recipient.